PROJECT SUMMARY/ABSTRACT The Markey Cancer Center's Cancer Cell Biology and Signaling (CS) Research Program includes a robust array of thematically driven projects performed by a cohesive and highly collaborative group of investigators. The overarching goal is to better understand cancer signaling networks in order to identify novel targets that can be exploited to create new therapeutic combinations. To achieve this objective, the CS program is divided into 3 thematic areas: 1) Aberrant proliferation and survival networks, 2) Determinants of tumor progression and metastasis, and 3) Interaction of tumor cells with their microenvironment. Inter-related subthemes within each goal reflect the scope of the research projects and individual expertise across the cross-cutting topic of ?Cell Signaling.? These include regulation of oncogene/tumor suppressor and kinase/phosphatase gene networks (Theme 1); contribution of cell motility/ epithelial-mesenchymal transition and cancer stem cells to therapeutic resistance (Theme 2); and examination of cellular and matrix contributions to cancer development and progression (Theme 3). Members of the CS program are experts in defining cancer signaling pathways that underlie the mechanisms of cancer cell survival, proliferation, invasion, and metastasis, and deciphering the relationship between the tumor and the micro- and macro-environments that modulate the dynamics of tumor progression. CS members include leaders in the field of survival/apoptosis signaling in response to growth factors/cytokines, adhesion, and anoikis, as well as experts in the processes of epithelial-mesenchymal transition, cell motility, and invasion. The 26 members of the program represent 3 colleges at the University of Kentucky and 9 different departments, reflecting diverse disciplinary perspectives that provided significant new insights into CS program thematic areas. The CS program has a total annual external cancer-related funding of $7.4M ($5.1M annual direct costs, of which $2.4M (48%) is from the National Cancer Institute). Members published 231 publications between 2013 and 2017, of which 90 (39%) are inter-programmatic, 55 (24%) are intra-programmatic, and 134 (58%) are inter-institutional. Led by CS program Co-leaders, Drs. Vivek Rangnekar (an expert in studying cell survival and apoptosis) and Rina Plattner (an expert in tumor invasion and metastasis), CS research focuses on reducing the most serious cancer burdens in Kentucky by identifying novel therapeutic targets in signaling pathways that drive cancer development and progression. In collaboration with other program leaders and Associate Directors for Basic Research and Clinical Translation, research of the CS program has led to 2 new clinical trials and eight new patents. Additionally, working with the Associate Director for Cancer Education and Mentoring, the Co-leaders of the CS program have instituted a robust mentoring system to ensure the success of junior faculty. By bringing a wide array of expertise and programmatic strengths, the CS program collectively provides a rich environment to facilitate multidisciplinary collaboration and builds a productive pipeline for translation of CS science into the clinic.